The Alzheimer's Disease Project

This project includes both a basic science component (discovery of molecular and cellular mechanisms of neuronal dysfunction and death) and a translational component (preclinical and clinical evaluation of novel interventions). The figure below includes many of the processes we and others have implicated in the pathogenesis of AD.

4b. γ-secretase mediates oxidative stress-induced ß-secretase expression in AD. Brain cells are subjected to oxidative stress during aging and more so in AD (Figure 5). We found that oxidative stress fails to induce BACE1 expression in presenilin-1 (γ-secretase)-deficient cells and in normal cells treated with γ-secretase inhibitors (23). Oxidative stress-induced ß-secretase activity and sAPPß levels were suppressed by γ-secretase inhibitors. Levels of γ- and ß-secretase activities were greater in brain tissue samples from AD patients compared to non-demented control subjects, and the elevated BACE1 level in the brains of 3xTgAD mice was reduced by treatment with a γ-secretase inhibitor. Our findings suggest that g-secretase mediates oxidative stress-induced expression of BACE1 resulting in excessive Aß production in AD.

4c. FAD presenilin-1 mutation impairs cholinergic modulation of hippocampal plasticity. We found that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice (67). Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca2+chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3xTgAD mice with PS1, APP and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of Aß and tau pathologies.

4d. TLR4 plays a role in Aß-induced neuronal death. We found that TLR4 expression increases in neurons when exposed to Aß1-42 or the lipid peroxidation product 4-hydroxynonenal (HNE) (65). Neuronal apoptosis triggered by Aß and HNE was mediated by JNK; neurons from TLR4 mutant mice exhibited reduced JNK and caspase-3 activation and were protected against apoptosis induced by Aß and HNE. Levels of TLR4 were decreased in inferior parietal cortex tissue specimens from end-stage AD patients compared to aged-matched control subjects, possibly as the result of loss of neurons expressing TLR4. Our findings suggest that TLR4 signaling increases the vulnerability of neurons to Aß and oxidative stress in AD, and identify TLR4 as a potential therapeutic target for AD.

4e. Evidence for the involvement of defective DNA repair in AD. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls (70). BER activities were also measured in brain samples from 9 amnestic mild cognitive impairment (MCI) subjects. We found significant BER deficiencies in brains of AD patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by DNA polymerase beta. The BER impairment was not restricted to damaged brain regions and was also detected in the brains of MCI patients, where it correlated with the abundance of neurofibrillary tangles. These findings suggest that BER dysfunction is a general feature of AD brains which occurs relatively early in the disease process.

4f. Dietary energy restriction, paroxetine and diazoxide forestall disease processes in 3xTgAD mice. We found that ADF, 40% CR, and treatment with the serotonin-selective reuptake inhibitor peroxetine, attenuate age-related cognitive impairment in 3xTgAD mice (19, 46). Interestingly, whereas 3xTgAD mice in the CR group showed lower levels of Aß1-42 and phospho-tau in the hippocampus compared to the control diet group, 3xTgAD mice in the ADF group did not. The latter result suggests that ADF protects neurons against adverse effects of Aß and tau pathologies on synaptic function, a possibility consistent with our hormesis hypothesis for the general mechanism of action of ADF (Figure 1). Because compromised cellular energy metabolism, cerebral hypoperfusion and neuronal calcium dysregulation are involved in the pathological process of AD, we evaluated the therapeutic potential of the KATP channel activator diazoxide in the 3xTgAD mouse model of AD. 3xTgAD mice treated with diazoxide for 8 months exhibited improved performance in a learning and memory test, reduced levels of anxiety, decreased accumulation of Aβ oligomers and hyperphosphorylated tau in the cortex and hippocampus, and increased cerebral blood flow. Thus, diazoxide can ameliorate molecular, cytopathological and behavioral alterations in a mouse model of AD suggesting a therapeutic potential for drugs that activate KATP channels in the treatment of AD.